Blocking TLR2 activity attenuates pulmonary metastases of tumor.
Blocking TLR2 activity attenuates pulmonary metastases of tumor.
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阻断 TLR2 活性可减轻肿瘤的肺转移。
DOI：
10.1371/journal.pone.0006520
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发表时间：
2009-08-05
期刊：
影响因子：
3.7
通讯作者：
Hu ZW
中科院分区：
文献类型：
--
作者：
Yang HZ;Cui B;Liu HZ;Mi S;Yan J;Yan HM;Hua F;Lin H;Cai WF;Xie WJ;Lv XX;Wang XX;Xin BM;Zhan QM;Hu ZW
转移是癌症患者死亡的最关键原因。免疫耐受在肿瘤进展和转移中起着至关重要的作用。在这项研究中，我们研究了TLR 2信号转导在静脉注射B16黑色素瘤细胞的小鼠模型中对肿瘤转移的潜在作用和机制。多种TLR亚型在B16细胞和几种人类癌细胞系上表达; TLR 2介导这些细胞的侵袭活性。高转移B16细胞比低转移B16-F1细胞释放更多的热休克蛋白60。重要的是，由肿瘤细胞释放的热休克蛋白60引起TLR 2的持续活化，并且在转录因子Stat 3的组成性活化中至关重要，导致免疫抑制性细胞因子和趋化因子的释放。此外，靶向TLR 2通过逆转B16细胞诱导的免疫抑制微环境和恢复肿瘤杀伤细胞如CD 8 + T细胞和M1巨噬细胞，显著减少肺转移并增加携带B16的小鼠的存活率。将抗TLR 2抗体和细胞毒性剂吉西他滨组合，进一步改善了荷瘤小鼠的存活率。我们的研究结果表明，TLR 2是一个有吸引力的目标，对转移和靶向免疫抑制微环境使用抗TLR 2抗体是一种新的治疗策略，打击危及生命的转移。
Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis. In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8+ T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice. Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.
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DOI：
10.1196/annals.1415.044
发表时间：
2007-01-01
期刊：
THYMOSINS IN HEALTH AND DISEASE: FIRST INTERNATIONAL SYMPOSIUM
影响因子：
--
作者：
Garaci, Enrico;Favalli, Cartesio;Rasi, Guido
通讯作者：
Rasi, Guido
影响因子：
5.8
作者：
Huang, SC;Ho, CT;Lin, JK
通讯作者：
Lin, JK
影响因子：
2.9
作者：
Knorr, Carolin;Huebschle, Thomas;Roth, Joachim
通讯作者：
Roth, Joachim
影响因子：
11.2
作者：
Huang, B;Zhao, J;Xiong, HB
通讯作者：
Xiong, HB
影响因子：
4.4
作者：
Lian, XM;Qin, YL;Yan, C
通讯作者：
Yan, C